Regarding the relationship between arteriosclerotic diseases and serum lipoprotein, it has been considered for some time that a certain relationship exists from the results of many epidemiological researches. For example, Badimon et al. (J. Clin. Invest., 85, 1234-1241 (1990)) reported that intravenous injection of fractions containing HDL (high density lipoprotein) and VHDL (very high density lipoprotein) to cholesterol-loaded rabbits resulted in the observation of not only prevention of progression of arteriosclerotic lesion but also regression thereof, and HDL and VHDL are considered to have an anti-arteriosclerotic action in the relationship between arteriosclerotic diseases and serum lipoprotein.
In recent years, the presence of a protein that transfers lipid between blood lipoproteins, or CETP (cholesteryl ester transfer protein), has been clarified. The presence of CETP was first pointed out in 1965 by Nichols & Smith (J. Lipid Res., 6, 206, 1965), and thereafter its cDNA was cloned in 1987 by Drayna et al. The molecular weight thereof is 74,000 Da as glycoprotein and about 58,000 Da when sugar chain is completely cleaved. Its cDNA consists of 1656 residues and encodes 476 amino acids following 17 signal peptides. Since about 44% thereof consists of hydrophobic amino acids, it has extremely high hydrophobicity and is easily inactivated by oxidation. In addition, it has been confirmed that CETP is produced in the organs such as liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle, heart muscle and the like, and produced in cells of the cell types of human monocyte-derived macrophage, B lymphocyte, fat cell, small intestinal epithelial cell, CaCo2 cell, hepatocyte (exemplified by human liver cancer cell-derived cell line, HepG2 cells) and the like. Besides the above-mentioned tissues, it is present in cerebrospinal fluid and semen, and its presence has been confirmed in culture media of human neuroblastoma and neuroglioma cells, choroid plexus of sheep and the like.
It has been also clarified that CETP is involved in the metabolism of any lipoprotein in living organisms, and has a major role in the reverse cholesterol transfer system. Namely, CETP has drawn attention as a mechanism for preventing accumulation of cholesterol in peripheral cells and preventing arteriosclerosis. In fact, with regard to HDL having an important role in this reverse cholesterol transfer system, a number of epidemiological researches have shown that a decrease in CE (cholesteryl ester) of HDL in blood is one of the risk factors of coronary artery diseases. It has been also clarified that the CETP activity varies depending on the animal species, wherein arteriosclerosis due to cholesterol-loading is hardly induced in animals with lower activity, and in reverse, easily induced in animals with higher activity, and that hyper-HDL-emia and hypo-LDL (low density lipoprotein)-emia are induced in the case of CETP deficiency, thus rendering the development of arteriosclerosis difficult, which in turn led to the recognition of the significance of blood HDL, as well as significance of CETP that mediates transfer of CE in HDL into blood LDL.
Free cholesterol (FC) synthesized in and secreted from the liver is taken up by very low density lipoprotein (VLDL). Then, due to the action of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), VLDL is metabolized in blood into LDL via intermediate density lipoprotein (IDL). LDL is taken up by peripheral cells via an LDL receptor and FC is supplied to the cells. Conversely from such flow from the liver to the peripheral cells, there exists a flow of cholesterol from peripheral cells toward the liver, which is called a reverse cholesterol transfer system. In other words, FC accumulated in the peripheral tissues is drawn by HDL, further esterified on HDL by the action of LCAT (lecithin-cholesterol acyltransferase) to form CE, and transferred to the hydrophobic core part of HDL, whereby HDL matures into spheric HDL particles. CE in HDL is transferred by CETP present in blood to apoB-containing lipoproteins such as VLDL, IDL, LDL and the like, and in return, TG is transferred to HDL at a molar ratio of 1:1. CE transferred to apoB-containing lipoprotein is taken up by the liver via LDL receptor in the liver, thereby indirectly transferring cholesterol to the liver. Moreover, there is a mechanism in which HDL takes up apoprotein E secreted from macrophage and the like to become apoprotein E-containing HDL rich in CE, and then is directly taken up by the liver via LDL receptor or remnant receptor. There also exists a path in which HDL particles are not taken up by the liver and only CE in HDL is selectively taken up by hepatocytes. Furthermore, another path exists in which HDL particles are taken up by hepatocytes via what is called an HDL receptor in the liver.
Namely, in the state of enhanced CETP activity, since CE transfer from HDL increases, CE in HDL decreases, and CE in VLDL, IDL and LDL increases. When take up of IDL and LDL by the liver increases, down-regulation is imposed on the LDL receptor, and LDL in blood increases. In contrast, in the CETP deficient state, HDL draws cholesterol from peripheral cells with the aid of LCAT, gradually increases its size and acquires apo E. Then, apo E-rich HDL is taken up by the liver via LDL receptor in the liver and catabolized. However, since this mechanism does not function sufficiently in human, large HDL dwells in the blood. Consequently, cholesterol pool in the liver becomes smaller and up-regulation is imposed on the LDL receptor, thereby decreasing LDL. Accordingly, selective inhibition of CETP can lower IDL, VLDL and LDL that promote arteriosclerosis and increase HDL that acts suppressively thereon, and produces expectation for the provision of an unprecedented prophylactic or therapeutic agent for arteriosclerosis or hyperlipidemia.
While many attempts have been made in recent years to develop a drug that inhibits such activity of CETP, a compound having a satisfactory activity has not been developed yet.
Meanwhile, many reports have been found recently on the compounds aiming at inhibiting such activity of CETP. For example, Biochemical and Biophysical Research Communications 223, 42-47 (1996) discloses dithiodipyridine derivatives, substituted dithiodibenzene derivatives and the like as compounds that inactivate CETP by modifying cysteine residue. However, this reference does not contain any description of the compound of the present invention, not to mention a description suggestive thereof.
In addition, WO95/06626 discloses Wiedendiol-A and Wiedendiol-B as CETP activity inhibitors. However, this publication does not contain any description suggesting the compound of the present invention.
Moreover, JP-B-45-11132, JP-B-45-2892, JP-B-45-2891, JP-B-45-2731 and JP-B-45-2730 disclose mercaptoanilides substituted by higher fatty acid such as o-isostearoylaminothiophenol and the like, as a compound having an action to prevent arteriosclerosis. However, these publications only mention the presence of an effect to prevent arteriosclerosis and lack description of Experimental Example that support the effect, much less a description of inhibition of CETP activity. Moreover, no description is found that suggests the compound of the present invention.
JP-T-2001-512416 (WO98/04528) discloses a biaryl compound that inhibits CETP. However, this publication has no description that suggests the compound of the present invention.
WO00/17164, WO00/17166 and WO01/40190 disclose 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline as a CETP inhibitor. However, these publications contain no description that suggests the compound of the present invention.
On the other hand, various compounds having a structure like the compound of the present invention have been reported. For example, JP-A-2001-106666 and WO01/10825 disclose carbamate derivatives characterized in that phenyl group has an oxime ether group. However, the compounds of these publications are compounds useful as antimicrobial agents for agriculture or gardening, and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO00/69810 discloses compounds such as 3-(4-{[N-[3-(2,6-dichlorophenyl)acryloyl]-N-(4-tert-butylbenzyl)amino]methyl}benzoylamino)propionic acid and the like. However, the compound of this publication is useful as a glucagon antagonist, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/67204 discloses compounds such as 1-[N-(4-chlorobenzyl)-N—(N,N-dimethylcarbamoyl)aminomethyl]-4-guanidinomethylbenzene and the like. However, the compound of this publication is useful as an analgesic, and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/44987 and U.S. Pat. No. 6,218,426 disclose compounds such as N-(4-tert-butylbenzyl)-N-[4-(guanidinomethyl)benzyl]benzamide and the like useful as a gonadotropin-releasing hormone antagonist/agonist. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 5,834,514 and JP-T-9-512556 (WO95/29672) disclose that halomethylamide compounds such as N-benzyl-N-(2,4-dichlorobenzyl)chloroacetamide and the like are useful as IL-1β protease activity inhibitors. However, these publications lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO97/24328 discloses 2-amino-heterocyclic compounds such as N,N-bis(2,4-dimethoxybenzyl)-N′-(4-methoxyphenyl)urea and the like. However, the compound of this publication is useful as a leukotriene synthesis inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO96/10559 discloses urea derivatives such as 1-benzyl-1-[3-(pyrazol-3-yl)benzyl]-3-(2,4,6-trimethylphenyl)urea and the like. However, the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,623,662 discloses that urea compounds such as 1-benzyl-1-(2,4-dichlorobenzyl)-3-(2,4-dimethylphenyl)urea and the like are useful as acyl-CoA:cholesterol acyltransferase inhibitors. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,473,579 discloses urea compounds such as 1,1-dibenzyl-3-(2,4-dimethylphenyl)-3-phenylurea and the like. However, the compound of this publication is useful as an acyl-CoA:cholesterol acyltransferase inhibitor and this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
U.S. Pat. No. 4,122,255, U.S. Pat. No. 4,064,125, U.S. Pat. No. 4,151,354 and U.S. Pat. No. 4,127,606 disclose compounds such as N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]-3-phenyl-N-(phenylmethyl)-2-propenamide and the like. However, the compounds of these publications are useful as antiinflammatory agents and they lack a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof.
WO99/18066 discloses amide carboxylic acid compounds such as ethyl 2-butyl-3-[4-[2-[N-benzyl-(4-pyridin-2-yl)amino]ethoxy]phenyl]propionate and the like having useful lipid-lowering action and the like. However, this publication lacks a disclosure of usefulness as a CETP activity inhibitor, or even a description suggestive thereof. Moreover, this publication lacks a disclosure of a structure such as the compound of the present invention, or even a description suggestive thereof.
In contrast, WO00/18724 discloses a compound having a structure similar to that of the present invention and a CETP inhibitory activity. To be specific, the following formula is disclosed.
When R2 and R3 form a hetero ring or cycloalkenyl in combination, the compound is structurally similar to the present invention. However, this invention lacks a concrete disclosure (Example) of ring B as shown in the present invention. In addition, this invention is distinct from the present invention in that the invention always has R1 (haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkenyloxyallyl).
In other words, this invention does not disclose a concrete structure as the compound of the present invention, not to mention a description suggestive thereof.